Detoxification of dithiophosphoric esters

ABSTRACT

Described is a method of reducing the toxicity to warm-blooded animals of dithiophosphoric esters of the formula: ATOMS, R&#39;&#39; phenyl or carboethoxymethyl. The method consists substantially in adding to the above esters, either undiluted or in solution, adequate quantities of acyl bromides or iodides.

United States Patent Santi Sept. 5, 1972 DETOXIFICATION OF DITHIOPHOSPHORIC ESTERS [72] Inventor: RomanoSanti,Milan,ltaly [73] Assignee: Montecatini Edison S.p.A., Milan,

Italy Filed: June 17, 1969 Appl. No.: 834,175

Foreign Application Priority Data References Cited UNITED STATES PATENTS 2,879,284 3/ 1959 2,962,521 11/1960 Usui ..260/989 2,980,723 4/1961 Frank et al. ..260/989 Primary Examiner-Joseph Rebold Assistant Examiner-Richard L. Raymond Attorney-Curt M. Avery, Arthur E. Wilfond, Herbert L. Lerner and Daniel J. Tick [57] ABSTRACT Described is a method of reducing the toxicity to warm-blooded animals of dithiophosphoric esters of the formula:

CHaO

3 3 ial y ith 9rb2 atoms, R'=phenyl or carboethoxymethyl. The method consists substantially in adding to the above esters,

either undiluted or in solution, adequate quantities of acyl bromides or iodides.

7 Claims, No Drawings Divine et a1. ..260/989 markedly reduces the toxicity of dithiophosphoric.

esters to warm-blooded animals.

In particular, the method of this invention can be profitably applied to products in the class defined by the formula:

CHQO

PSCH--GOOR OHM R wherein R=alkyl with a linear or branched chain containing one to five carbon atoms, R=phenyl or carboethoxyrnethyl.

The present method substantially consists in treating the technical grade products, whose toxicity to warmblooded animals is to be reduced (detoxification), with bromides or iodides of aliphatic or aromatic organic acids. This is quite unforeseable and peculiar to acyl bromides and iodides, as the corresponding chlorides do not exercise any action at all. The method of this invention is extremely simple, since it consists in adding to the product to be detoxified or to solutions containing said product, small quantities of acylic bromide and/or iodide dissolved in inert organic solvents, while stirring the whole for variable periods of time, depending on temperature, and finally removing the excess of acylic halides and volatile substances, if any. There occurs practically no loss of product or decrease in content.

As is well known to those skilled in the art, the evaluation of a pesticide is not based only on its activity against pests, but also on its toxicity to warm-blooded animals. This is not only in relation to the hazards, which may arise when handling pesticides during their application, but especially to the possible effects which may be exerted on humans when these products are used for agricultural purposes, because of their residues remaining on crops intended for consumption as food or in places where such pesticides are employed for household and public health uses. Consequently, there is a strong tendency towards employing substances which, for equal efficiency, have the lowest toxicity to warm-blooded animals. It must be emphasized, moreover, that if a product can be provided with a lower toxicity to warm-blooded animals, it can be used in field in which it would be otherwise precluded.

It is therefore evident that the discovery of a simple and inexpensive method to reduce the toxicity to warm-blooded animals, like the one covered by this invention, is very useful and a substantial contribution to technical progress in the specific field of pesticides.

The compounds under the above formula have long been known as pesticides, and some of them are currently in use, as for example ethyl mercaptophenyl acetate 0,0 dimethyl phosphorodithioate (Cidial) and 0,0 dimethyl S (1.2 dicarboethoxyethyl) dithiophosphate (Malathion).

The toxicity to warm-blooded animal of the compounds in the class concerned varies significantly with the method of preparation and also, in some cases, from one operation to another in the same process. It should also be noted that even highly pure products,

e.i., with a high percentage of active ingredient, do not always reach a satisfactory level as far as their toxicity to warm-blooded animals is concerned.

This is clearly due to the fact that extremely small quantities of particular substances are sufficient to increase to a large extent the toxicity to warm-blooded animals.

The method of this invention does not involve the process for the preparation of products with a particularly high degree of purity in order to reach a satisfactory toxicity level for warm-blooded animals. On the other hand, these products, as already stated, do not always have the necessary characteristics as regards their toxicity to warm-blooded animals.

This aspect of the invention is particularly important from the technical and economic standpoint. Ethyl mercaptophenyl acetate 0,0 dimethyl dithiophosphate (hereinafter briefly referred to as Compound I), technical product, has an average toxicity between 200 and 1,000 mg/kg. The formula of this compound is:

CHaO

P-S-CH-C .0 O C2115 C1130 CaHs Technical products of 0,0 dimethyl S (1,2 dicarboethoxyethyl) dithiophosphate (hereinafter briefly referred to as Compound II), with a toxicity to warmblooded animals ranging from about 1,000 mg/kg to 2,500 mg/kg, are available on the market.

The formula of this compound is:

Isopropyl mercaptophenyl acetate 0,0 dimethyl dithiophosphate (hereinafter briefly referred to as Compound III) has a toxicity to warm-blooded animals between 210 and 1,100 mg/kg.

The formula of this compound is:

ll CHaO S CnHll According to the process of this invention, even from products with lowest toxicity values, it is possible to obtain products with a toxicity of more than 2,000 mg/kg.

In French Patent Specification No. 1,507,651, is described a process consisting essentially of a treatment with adsorbing agents and the removal of the volatile substances contained in the dithiophosphoric ester, which makes it possible to markedly reduce in Compound I and like products the toxicity to warmblooded animals.

The method of this invention is completely different and simpler from a technological point of view. In the precess according to this invention, as already said, the acylic bromides and/or iodides can be added directly to the product to be treated, or to solutions of said product in inert organic solvents. Detoxification can decomposition does not occur or remains within acceptable limits, in order to obtain the best result in the shortest possible time. Consequently, it is not difficult is removed together with the for those skilled in the art, to establish, in each single solvent by the usual techniques. However, if the 5 case, the temperature and duration most convenient -blooded for the treatment. Excellent results can be obtained with the use of halides of aliphatic acids having a short chain of carbon atoms, such as, for example, acetyl bromide or iodide, or a long one, like stearoyl bromide thereafter to remove the solvent and the volatile subor iodide, or of aromatic acids like benzoyl bromide or iodide. The choice of one or the other of these means may be made according to which is the most convenient.

5 The quantities of acylic halides, which are used in the treatments, are not significant; on an average, quantities ranging between 0.5 and 2 percent are sufficient.

100 C.). The table hereinafter, which is reported merely to illustrate and not to limit the invention in any way, contains data obtained in detoxification tests.

Initial Percent oral LD Oral ingredient active for rat, LD 50 after desubstance mgJkg. Length of 'Iemp., for rat, toxlfication (d=1%) Acyllc halide, percent by weight treatment C. mgJkg. (=l=l%) therefore be suitably carried out during production itself, namely, in its final stage, when solution of the product is achieved. The excess of acylic halides or volatile substances, if any,

product being treated has a toxicity to warm animals, at the highest possible level or almost so, it is best carrying out the treatment with acylic bromides or iodides on the product dissolved in a solvent and stances by distillation in a countercurrent of steam.

Temperature is not exactly critical since a fair degree of detoxification can be reached even at room temperature. The duration of the treatment depends on temperature and decreases as the latter increases.

Since, as is well-known, the dithiophosphoric esters of the class considered, if maintained for a long time at rather high temperatures (for example tend to decompose, those skilled in the art will operate in each single case at the temperature at which such Product mwwmmwwmmmmmwwwmm m mmmmm% mmwmmmwmwmwmwm m m mwmm wmmwmwwmw Wm H a mmmmmm wwawwwwwmwmwww n n m P m ma; u 1( n m m m n n u u u n w t n n u n H n n u n m mmmmmmmm n U u n u n u e 0 V w mw wm 0 0 mmmmmmwmmmmmmmmmmm w m m mmmmmmmmmmmmmmwmmm mmm. m 11L.212|3, L m w 2 2 2 2 2 2 2 aw& l2 awqwowowow2 2 2 2 qw1w .1 mmamw Mmm a m m m mmwa mmmwmmwwmmmmmm 92D 22 o 9235, 6 x C 222 222 8 22222 w 25 C WHM( D. wmwmmmwmmmm m22%%w a al m a P m m a v 7 I 0 V U m m mm mmmmwmmwmmwwmm mm H n m m w m 2 &Z2 2 ZL2 2 LL2 && mm n m mm m m h m .v." ee hhh d h h nnnnnnnmnhhhna ma no wnmww mwm Ln mlzramsw 2 2 24744444444475MQ64 mo u u u n n 8 t n a n T W n H n u u e 0 r O 0 o 0 n u n n u u u a W n W W n W ....1 a ."SILL. D. 8" e 8M ma :syyyn d" m m d. et v.aaa d .1. m m n" u. mun m... m. n u n wm 0 .nhhhhh t o u m m m u u u "m mom u4s11mm124112 m. m u b b m c m :mn tram; mm mm m e a W amun m mm W w W n 0 m w m m m m a mm m an??? fi A A" i I p a l r mm m mmmm hw m m mm m m Man mm m mm m r rwbbpb mm m u m u u n n t b .D l l W. .D 0.. n f 11 1 11 1 1 1 w mmrwmw m ao mamm m wmmm w m w mmueba r m "w u n n 0 mmm m w A u n n I mmmw mmmwwwwmwwwwmwwwwwmmmm .7 1 aw mam mmmmmmwm aaaaaaa a 1111. m 111 P i nnflwnmnmflwfle nm wnmfi flwoooooo emwlml wwwwwlllllllllll m wwwwmwmmwmwmwmmwwm mmmW wwmmmmmw mw v m 6 8% i n P n. H n i n m n u a n I d d n W n w a a w P u .w n. m d 0 m 0 m r o C P P C Perctiant v Percent Initial Oral ingre dlen active oral LD 50 LD 50 alter detoxiingredient for rat, Acylie halide, Length of Temp., [or rat, fleation Product (=|=1%) mg./kg. percent by weight treatment C. mgJkg. (i1%) s t Compound III 92. 3 650 Acetyl bromide 1%.... 5 days 26 2, 670 92.10

D0 92.3 650 ..do 2h 80 2,200 91.40 Do 92.3 650 ...do 4h 80 2,200 92,00 Do 92.3 650 -...-do 7h 80 2,000 92.50

(+) The LD 50 values were obtained by administering the product undiluted, via a stomach tube, to a mixed population (M 3:26, 0) of adult albino rats weighing 100 g.

mg/kg) containing 88 percent active ingredient. The

reactor was heated by circulating hot water up to about 55 C. 310 g acetyl bromide are added, while stirring. The temperature was raised to 80 C. and was kept at this level for 3 hours and 45 minutes. The vacuumpump was operated and the mass further stirred under vacuum at 2 mm/Hg for 15 minutes. Finally, the reactor was cooled to room temperature by circulating cold water. The product obtained, without loss in weight, has an oral toxicity for the rat of 2700 mg/kg and an 88 percent content.

11 When producing Compound I on an industrial 105 kg of product were obtained and dissolved in 160 kg dichloroethane. This solution was heated to 55 C. and 1.05 kg acetyl bromide were added. The mass was heated to 80 C. and was kept at this temperature for 2 hours, while stirring. The solution was then distilled in a column in countercurrent of steam. The solvent, which was not miscible with water, was recovered by condensation. The ester, in which some water was still dispersed, was allowed to decant and then dried under vacuum at 50 60 C., after separation of the aqueous phase. 102 kg of product at 92 percent active ingredient and an oral LD 50 for the rat of 2,500 mg/kg were obtained. A sample of the product derived from the dichloroethane solution by vacuum evaporation at 40 C., before the addition of acetyl bromide, was found to contain 91.8 percent active ingredient with an oral LD 50 for the rat of 800 mg/kg.

III If the ester to be detoxified has a high toxicity level, it is best using the detoxifying method described hereinafter. A flask with a l-l capacity, provided with a reflux condenser and a water-circulation heating or cooling jacket was fed with 294 g of Compound I, at 88.5% active ingredient (oral LD 50 for the rat 250 g/kg) dissolved in 445 g dichloroethane. 3 g acetyl bromide are added. The temperature was raised to 80 C. and the mass was stirred for 2 hours. Finally, the solvent and the volatile substances are removed by distiliation in a counter-current of steam. 274 g of product with an oral LD 50 for the rat of 2,500 mg/kg and an active ingredient content of 94.5 percent were obtained.

iclaim:

l. The method of reducing the toxicity of warmblooded animals of dithiophosphoric esters of the formula:

CHiO

P-S-CH-COOR cmo wherein R =alkyl with one to five carbon atoms R phenyl or carboethoxymethyl which comprises adding to the above esters, an acyl halide of the formula:

0 ZJLX whereinX=Br orland Z alkyl or bromo alkyl with one to 20 carbon atoms, phenyl, maintaining the mass at -90, for periods between half an hour and 5 hours, removing the excess of acylic halide and volatile substances, which may be present under vacuum or by distillation in a countercurrent of steam.

2. The method of claim 1, wherein the dithiophosphoric ester is ethyl mercaptophenyl acetate 0,0 dimethyl dithiophosphate.

3. The method of claim 1, wherein the dithiophosphoric ester is 0,0 dimethyl S (1,2 dicarboethoxyethyl) dithiophosphate.

4. The method of claim 1, wherein the dithiophosphoric ester is isopropyl mercaptophenyl acetate 0,0 dimethyl dithiophosphate.

5. The method of claim 1, wherein the dithiophosphoric ester is ethyl mercaptophenyl acetate 0,0 dimethyl dithiophosphate, the acyl halide is acetyl bromide in a proportion of 1 percent, the temperature is -90 C. and the duration of the treatment is between 2 and 4 hours.

6. The method of claim 1,

wherein the dithiophosphoric ester is isopropyl mercaptophenyl I acetate 0,0 dimethyl dithiophosphate, the acyl halide is acetyl bromide in a proportion of 1 percent, the temperature is 80 C. and the duration of the treatment is 4 hours.

7. The method of claim 1, wherein the dithiophosphoric ester is 0,0 dimethyl S (1,2 dicarboethoxyethyl) dithiophosphate, the acyl halide is acetyl bromide in a proportion of 2 percent, the temperature is 80 C. and the duration of the treatment is half to one hour. 

2. The method of claim 1, wherein the dithiophosphoric ester is ethyl mercaptophenyl acetate O,O dimethyl dithiophosphate.
 3. The method of claim 1, wherein the dithiophosphoric ester is O,O dimethyl S (1,2 dicarboethoxyethyl) dithiophosphate.
 4. The method of claim 1, wherein the dithiophosphoric ester is isopropyl mercaptophenyl acetate O,O dimethyl dithiophosphate.
 5. The method of claim 1, wherein the dithiophosphoric ester is ethyl mercaptophenyl acetate O,O dimethyl dithiophosphate, the acyl halide is acetyl bromide in a proportion of 1 percent, the temperature is 80* - 90* C. and the duration of the treatment is between 2 and 4 hours.
 6. The method of claim 1, wherein the dithiophosphoric ester is isopropyl mercaptophenyl acetate O,O dimethyl dithiophosphate, the acyl halide is acetyl bromide in a proportion of 1 percent, the temperature is 80* C. and the duration of the treatment is 4 hours.
 7. The method of claim 1, wherein the dithiophosphoric ester is O,O dimethyl S (1,2 dicarboethoxyethyl) dithiophosphate, the acyl halide is acetyl bromide in a proportion of 2 percent, the temperature is 80* C. and the duration of the treatment is half to one hour. 